Chromatin remodeling in the aging genome of Drosophila

Abstract

SummaryChromatin structure affects the accessibility of DNA to transcription, repair, and replication. Changes in chromatin structure occur during development, but less is known about changes during aging. We examined the state of chromatin structure and its effect on gene expression during aging in Drosophila at the whole genome and cellular level using whole-genome tiling microarrays of activation and repressive chromatin marks, whole-genome transcriptional microarrays and single-cell immunohistochemistry. We found dramatic reorganization of chromosomal regions with age. Mapping of H3K9me3 and HP1 signals to fly chromosomes reveals in young flies the expected high enrichment in the pericentric regions, the 4th chromosome, and islands of facultative heterochromatin dispersed throughout the genome. With age, there is a striking reduction in this enrichment resulting in a nearly equivalent level of H3K9me3 and HP1 in the pericentric regions, the 4th chromosome, facultative heterochromatin, and euchromatin. These extensive changes in repressive chromatin marks are associated with alterations in age-related gene expression. Large-scale changes in repressive marks with age are further substantiated by single-cell immunohistochemistry that shows changes in nuclear distribution of H3K9me3 and HP1 marks with age. Such epigenetic changes are expected to directly or indirectly impinge upon important cellular functions such as gene expression, DNA repair, and DNA replication. The combination of genome-wide approaches such as whole-genome chromatin immunoprecipitation and transcriptional studies in conjunction with single-cell immunohistochemistry as shown here provide a first step toward defining how changes in chromatin may contribute to the process of aging in metazoans.

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…A similar decrease in histone expression was also reported in human fibroblasts in culture (Dang et al 2009). A more recent study reports a significant age-associated decrease in the expression of H3K9me3 in drosophila (Wood et al 2010). In contrast, decreased heterochromatin-specific H3K9me3 due to reduced expression of the recruiting protein HP1 has been reported in aged humans (Scaffidi and Misteli 2006).…”

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

“…Moreover by modulating the expression of HP1, a protein required for the maintenance of heterochromatin, researchers have shown that increase or decrease HP1 levels leads to lifespan extension or shortening, respectively, in Drosophila (Larson et al ., 2012). Consistently, old Drosophila exhibits both HP1 reduction and the reduction of pericentric heterochromatin as judged by a decrease in H3K9me3 modification (Wood et al ., 2010; Larson et al ., 2012; Chen et al ., 2014). …”

Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span

“…To test whether H3K36me3 marks negatively associate with mRNA expression change during aging in different species, we examined H3K36me3 ChIP-chip data and RNA-seq data from young (10 d) and old (40 d) D. melanogaster female heads (Wood et al 2010). We analyzed the Drosophila data using the same methods described earlier for the C. elegans data and observed a very similar negative correlation between gene body H3K36me3 levels and age-dependent mRNA expression changes (Spearman's correlation test, ρ = −0.50; P-value < 0.001; and linear regression analysis, R 2 = 0.92) (Fig.…”